CN102716082A - Cefoxitin sodium liposome injection - Google Patents
Cefoxitin sodium liposome injection Download PDFInfo
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- CN102716082A CN102716082A CN2012102223575A CN201210222357A CN102716082A CN 102716082 A CN102716082 A CN 102716082A CN 2012102223575 A CN2012102223575 A CN 2012102223575A CN 201210222357 A CN201210222357 A CN 201210222357A CN 102716082 A CN102716082 A CN 102716082A
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Abstract
The invention discloses a cefoxitin sodium liposome injection and a preparation method thereof. The cefoxitin sodium liposome injection which is high in quality is prepared from cefoxitin sodium, phosphatidylserine, cholesterol, poloxamer 188, and trehalose in a specific weight ratio. Compared with the conventional preparation, the preparation has the advantages that the stability and the bioavailability of the preparation are greatly improved, the medicine is released stably, the quality of the preparation product is improved, the toxic and side effects are reduced, and the injection is obvious in curative effect.
Description
Technical field
The present invention relates to a kind of novel form of MK-306, be specifically related to a kind of lipidosome injection and method for making thereof of MK-306, belong to medical technical field.
Background technology
MK-306, its chemical name is: (6R, 7S)-3-［ (1-carbamyl oxygen) methyl ］-7-methoxyl group-8-oxo-7-［ 2-(2-thienyl) acetylamino ］-5-thia-1-azabicyclo ［ 4.2.0 ］ oct-2-ene-2-formic acid sodium salt, molecular formula: C
16H
16N
3NaO
7S
2, molecular weight 449.43, structural formula:
MK-306 is a beta-lactam antibiotic, by the exploitation of U.S. MSD Corp., and listing in 1974.Cefoxitin synthesizes and kill bacteria through suppressing bacteria cell wall; And because its structural characteristics make it have very high repellence to bacteriogenic beta-lactamase; The same second generation cephalosporin of antibacterial action and antimicrobial spectrum; But particularly the effect of bacteroides fragilis is stronger to anaerobe, and is stable to beta-lactamase.Be used for peritonitis and other intraperitoneal, interior, the gynecological infection of pelvic cavity, septicemia, endocarditis, urinary tract infection (comprising gonorrhea), respiratory tract infection, bone joint infection, skin soft-tissue infection clinically.
The therapeutic effect of MK-306 depends on the design to its pharmaceutical preparation to a great extent.Importantly, the form of the cefoxitin sodium compound of injection should provide high bioavailability, reaches maximization so that cefoxitin gets into the absorption of blood.
Patent documentation CN101780045A discloses a kind of cefoxitin sodium powder-needle preparation for injection and preparation method thereof, and it is processed through aseptic raw material MK-306 direct packaging; The sale of domestic existing cefoxitin sodium for injection at present, it also is that MK-306 is carried out simple packing.But the long-term shelf-stability of aseptic subpackaged powder of MK-306 is relatively poor, and content descends, and bioavailability is low.
Liposome (liposomes) is to be proposed by biomembranous models of conduct research such as Britain Banghan nineteen sixty-five the earliest.Be meant drug encapsulation made spherical targeted drug carrier formulation of superminiature in the middle of the thin film that the lipoids bimolecular forms, belong to a kind of novel form of targeting drug delivery system.Liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine like liposome, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce elimination speed in the body; Can protect the medicine that is wrapped effectively, improve bioavailability; Change medicine distribution in vivo, and can the release of targeting property, the toxic and side effects of medicine can be reduced; Be fit to multipath administration etc.
People are through discovering, liposome can be controlled the release of medicine as the carrier of medicine, improves drug targeting property, reduces drug toxicity and side effect, improves curative effect of medication.
In order to improve the bioavailability of MK-306, strengthen its targeting property, the inventor studies the lipidosome injection of cefoxitin sodium; Obtain unforeseeable effect, overcome a series of problems that existing cefoxitin preparation of sodium exists, improved the dissolubility and the stability of medicine; Prolong drug retention time is in vivo brought into play drug effect for a long time, improves bioavailability; Reduce toxic and side effects, reduce incidence rate of adverse reaction, improve treatment speed and therapeutic effect.
Summary of the invention
The challenge of preparation liposome is to select suitable liposome constituent and method for making.Because the character of liposome is directly closely related with the composition of liposome like stability, envelop rate, onset time, in vivo circulation time, bioavailability and toxic and side effects etc.; And the composition of liposome with the pharmaceutical properties that will seal directly closely related; Therefore, selecting which type of excipient to form the cefoxitin sodium lipidosome with better quality is the primary problem that solves of the present invention.
In order to form colory MK-306 lipidosome injection, can good compatible with MK-306 it well be sealed and non-leakage filmogen thereby importantly seek, and seek the excipient composition that can make liposome form the stable injectable agent.
To achieve these goals, big quantity research and test that the inventor carries out, MK-306, Phosphatidylserine, cholesterol, poloxamer 188, the trehalose of discovery specified weight proportioning can be processed the MK-306 lipidosome injection of excellent quality; Wherein, Envelop rate as the MK-306 of active constituents of medicine is high, and the liposome particle diameter is little and be evenly distributed, and compares with cefoxitin sodium injection of the prior art; The retention time significant prolongation of the active constituents of medicine of preparation of the present invention in the body circulation; The biocompatibility of medicine is high, and bioavailability obviously improves, and curative effect obviously improves.
Cefoxitin lipidosome injection described in the present invention, the specification of the MK-306 of its UD are 0.5g, 1.0g, 2.0g.
On the one hand, the present invention provides a kind of MK-306 lipidosome injection, and it is mainly processed by the composition of following weight portion proportioning:
Preferably, MK-306 lipidosome injection according to the present invention is mainly processed by the composition that comprises following weight portion proportioning:
As the phospholipid that is used to form liposome, can use natural phospholipid and synthetic phospholipid.Among the present invention, according to the characteristics of cefoxitin, find that soy phosphatidylserine is particularly suitable for as basic phospholipid filmogen, at first soy phosphatidylserine is as a kind of natural phospholipid, and its content is very high, obtains easily, and is cheap; Secondly, the phase transition temperature of soy phosphatidylserine is higher, is easy to form the stabilized liposomes film.
When using other phospholipid, be difficult to form colory liposome, character such as the envelop rate of liposome, stability and percolation ratio are poor.
In MK-306 lipidosome injection of the present invention, for the MK-306 of 1 weight portion, the consumption of soy phosphatidylserine is the 0.1-1 weight portion.If the consumption of soy phosphatidylserine is lower than 0.1 weight portion, then can't form stabilized liposomes; Otherwise if the consumption of the consumption of soy phosphatidylserine is higher than 1 weight portion, then the envelop rate as the MK-306 of active constituents of medicine descends, and the quality of injection and curative effect reduce.
In MK-306 lipidosome injection of the present invention, cholesterol and poloxamer 188 are used to regulate the membrane stability of liposome.
Cholesterol is a kind of amphiphilic, combines with soy phosphatidylserine, stops it to be condensed into crystal structure.Cholesterol mixes the soy phosphatidylserine bilayer, is similar to " buffer agent " and equally plays the effect of regulating membrane structure " flowability ".When being lower than phase transition temperature, cholesterol can make film reduce ordered arrangement, increases mobile; When being higher than phase transition temperature, cholesterol can increase the ordered arrangement of film, thereby reduces the flowability of film.Cholesterol can make liposome bimolecular tunic solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
Research shows that the stability of liposome and bioavailability have close corresponding relation.Stability is high more, and bioavailability is high more.Therefore, the stability of MK-306 lipidosome injection of the present invention is high, is to cause one of high factor of drug bioavailability.
On the other hand; The inventor discovers; In MK-306 lipidosome injection of the present invention, for the MK-306 of 1 weight portion, the consumption of soy phosphatidylserine is the 0.1-1 weight portion; When cholesterol was the 0.1-0.8 weight portion, the envelop rate of formed MK-306 lipidosome injection was high.
In MK-306 lipidosome injection of the present invention, use poloxamer 188 further to improve the stability of liposome membrane.Poloxamer 188 is a kind of novel non-ionic surface active agents; When being used for distearyl acid phosphatidylcholine duplicature; Can improve the chemical energy between this duplicature; Thereby improve the chemical stability of liposome in waterborne liquid, and then improve the stability of MK-306 lipidosome injection.
In MK-306 lipidosome injection of the present invention, for the MK-306 of 1 weight portion, the consumption of poloxamer 188 is the 0.5-1 weight portion.If the consumption of poloxamer 188 is lower than 0.5 weight portion; Then cause the stability improvement of cefoxitin sodium lipidosome injection not enough owing to its consumption is low excessively; Otherwise if the consumption of poloxamer 188 is higher than 1 weight portion, it is too high and cause liposome membrane to be easy to reveal then to be used for its consumption.
Discover that when the cefoxitin that uses above-mentioned specified quantitative, soy phosphatidylserine, cholesterol and poloxamer 188, can obtain colory cefoxitin sodium lipidosome, its envelop rate and stability are all very high, toxicity is low, the bioavailability height.
In MK-306 lipidosome injection of the present invention, use trehalose as excipient, be used to form stable injection.
MK-306 lipidosome injection of the present invention, wherein the specification of the MK-306 of UD is 0.5g, 1.0g, 2.0g.
On the other hand, the present invention also provides a kind of method for preparing of MK-306 lipidosome injection, specifically comprises being prepared as follows step:
(1) MK-306, soy phosphatidylserine, cholesterol and poloxamer 188 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) in bottle, add buffer solution, jolting was stirred 20 minutes; Rotating speed was 500-1000r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 5-10 minute; Rotating speed 10000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) add trehalose, stir, 0.45 μ m filtering with microporous membrane, packing, lid is rolled in lyophilization, promptly gets the MK-306 lipidosome injection, i.e. cefoxitin sodium lipidosome frozen powder for injection injection.
Above-mentioned described method for preparing, wherein said organic solvent is selected from one or more in ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, acetonitrile, benzyl alcohol, ethyl acetate, normal hexane and the dichloromethane, is preferably methanol.
Above-mentioned described method for preparing, wherein said buffer salt solution are selected from a kind of in PBS, citrate buffer solution, carbonate buffer solution, the borate buffer solution.
Above-mentioned described method for preparing, wherein said buffer salt solution are that pH is 6.8 PBS.
The challenge of preparation liposome is how to make liposome membrane to form the high vesicle of envelop rate of suitable size, appropriate configuration material.And these materials do not spill at the formation liposome.
The inventor has obtained colory MK-306 lipidosome injection through selecting suitable material composition, adopting suitable preparation technology, and the liposome particle diameter is little, and particle size distribution is even, and envelop rate is high, and stability is high.
Discover that the size of liposome is to influence the liposome principal element with the time of staying that distributes in vivo, the particle diameter of liposome is more little, and the time of staying is long more in the body.MK-306 liposome particles through the inventive method preparation is little, and particle size distribution is even, and this is one of its factor that metabolic rate is low in vivo, bioavailability is high.
Description of drawings
Below, specify embodiment of the present invention in conjunction with accompanying drawing, wherein:
Fig. 1 is the blood drug level-time graph of MK-306 lipidosome injection.
Wherein:
The specific embodiment
Following examples are to further specify of the present invention, but never limit the scope of the present invention.Further set forth the present invention in detail with reference to embodiment below, but it will be appreciated by those skilled in the art that the present invention is not limited to the method for preparing of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modification to the present invention according to description of the invention, but these all will comprise within the scope of the invention.
Embodiment 1 MK-306 lipidosome injection
Prescription:
Preparation technology:
(1) 500g MK-306,500g soy phosphatidylserine, 300g cholesterol and 400g poloxamer 188 are dissolved in the 5000ml methanol, mix homogeneously, methanol is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) pH that in bottle, adds 2000ml is 6.8 PBS, and jolting was stirred 20 minutes; Rotating speed is 500-1000r/min; Make the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 5-10 minute, rotating speed 10000r/min; With 0.45 μ m filtering with microporous membrane, make liposome turbid liquor;
(3) add the 400g trehalose, stir, 0.45 μ m filtering with microporous membrane, packing, lid is rolled in lyophilization, promptly gets 1000 bottles of MK-306 lipidosome injections.
Embodiment 2 MK-306 lipidosome injections
Prescription:
Preparation technology:
(1) 1000g MK-306,800g soy phosphatidylserine, 400g cholesterol and 600g poloxamer 188 are dissolved in the 8000ml methanol, mix homogeneously, methanol is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) pH that in bottle, adds 3000ml is 6.8 PBS, and jolting was stirred 20 minutes; Rotating speed is 500-1000r/min; Make the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 5-10 minute, rotating speed 10000r/min; With 0.45 μ m filtering with microporous membrane, make liposome turbid liquor;
(3) add the 500g trehalose, stir, 0.45 μ m filtering with microporous membrane, packing, lid is rolled in lyophilization, promptly gets 1000 bottles of MK-306 lipidosome injections.
Embodiment 3 MK-306 lipidosome injections
Prescription:
Preparation technology:
(1) 2000g MK-306,600g soy phosphatidylserine, 600g cholesterol and 1000g poloxamer 188 are dissolved in the 6000ml methanol, mix homogeneously, methanol is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) pH that in bottle, adds 3000ml is 6.8 PBS, and jolting was stirred 20 minutes; Rotating speed is 500-1000r/min; Make the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 5-10 minute, rotating speed 10000r/min; With 0.45 μ m filtering with microporous membrane, make liposome turbid liquor;
(3) add the 800g trehalose, stir, 0.45 μ m filtering with microporous membrane, packing, lid is rolled in lyophilization, promptly gets 1000 bottles of MK-306 lipidosome injections.
The preparation of Comparative Examples 1-3 MK-306 lipidosome injection
Adopt the production technology of embodiment 1, the composition in will the Comparative Examples 1-3 shown in following table 1-3 is processed the MK-306 lipidosome injection respectively:
Used composition among the table 1 Comparative Examples 1-3
Comparative Examples 1 is from the embodiment 1. of CN101669910B
Comparative Examples 2 is from the embodiment 1 of CN101637456B.
The mensuration of Test Example 1 liposome particle diameter
Under the room temperature condition; Get the cefoxitin lipidosome injection of embodiment and Comparative Examples; Be made into 0.1% solution with normal saline, place the sample cell of Submicron Particle Sizer Model 370 particle diameter detectors, measure particle size distribution and mean diameter; Observe particle shape with projection electron microscope.Result such as table 1:
Table 2 particle diameter testing result
Can know that by above result the cefoxitin sodium lipidosome particle diameter that embodiment 1-3 makes is even, show spherical, big or small homogeneous; The cefoxitin sodium lipidosome particle diameter that Comparative Examples 1-3 makes is inhomogeneous, and shape is indefinite, and is not of uniform size.
The mensuration of Test Example 2 envelop rates
The MK-306 Liposomal formulation of embodiment and Comparative Examples preparation is dissolved in water is diluted to 0.1% solution, high speed centrifugation, 5000r/min; Centrifugal 20 minutes, get supernatant, use dissolve with methanol; The HPLC method is measured the cefoxitin sodium content, the computational envelope rate, and result such as table 2:
Table 3 entrapment efficiency determination result
Can know that by table 3 envelop rate of the Liposomal formulation of embodiment 1-3 preparation is higher than the envelop rate of the Liposomal formulation of Comparative Examples 1-3 significantly.Explain that when the composition that uses beyond the used composition of the present invention perhaps work as the composition consumption outside the composition amount ranges that the present invention limits, the liposome encapsulation of gained liposome is lower than the present invention.
Test Example 3 study on the stability
Sample and listing cefoxitin sodium for injection (lot number: 20110904 with embodiment of the invention 1-3 and Comparative Examples 1-4 preparation; Hainan Xinshitong Pharmaceutical Co., Ltd) places following 6 months of the condition of 40 ℃ of high temperature, relative humidity 75% respectively; Carry out accelerated test and investigate, result of the test is shown in the following table 4.
Table 4 accelerated test result
Can be known that by above result when quickening June, Comparative Examples becomes pale yellow powder with the listing preparation, content reduces, and related substance raises; And sample character of the present invention, content and related substance variation are all not obvious, explain that product stability of the present invention is good.
The test of Test Example 4 percolation ratios
Get the sample of Test Example 1-3 and Comparative Examples 1-3 preparation, under the room temperature condition,, make regular check on respectively, measure envelop rate respectively at 0 day, 30 days, 60 days, 90 days and 180 days, with the dose of sealing in 0 day relatively, calculate percolation ratio, the result sees table 4
Table 5 percolation ratio result of the test
| Time | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative Examples 1 | Comparative Examples 2 | Comparative Examples 3 |
| 0 day | 0.37 | 0.36 | 0.43 | 1.80 | 1.51 | 121 |
| 30 days | 0.41 | 0.48 | 0.51 | 2.75 | 2.78 | 2.35 |
| 60 days | 0.59 | 0.67 | 0.65 | 4.53 | 4.46 | 5.03 |
| 90 days | 0.68 | 0.75 | 0.76 | 8.75 | 9.96 | 10.45 |
| 180 days | 0.83 | 0.96 | 0.91 | 15.97 | 18.59 | 19.57 |
Can know by above result of the test; The sample of embodiment of the invention preparation percolation ratio in long term storage is long changes little; And the sample percolation ratio of Comparative Examples increases gradually, and the liposome seepage is serious, and the MK-306 lipidosome injection of this explanation the present invention preparation has advantages of higher stability.
The mensuration of Test Example 5 blood drug level
42 rats are divided into 7 groups at random; Every group of injection for preparing among intravenous administration embodiment 1-3 and the Comparative Examples 1-3 respectively; And commercially available cefoxitin sodium for injection (lot number: 20110904, Hainan Xinshitong Pharmaceutical Co., Ltd), injection volume is the 10mg MK-306.Respectively at 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h and 24h, take a blood sample after the administration, blood sample is measured blood drug level with the HPLC-MS method after treatment.The MK-306 lipidosome injection for preparing among the MK-306 lipidosome injection for preparing among the drafting embodiment 1-3, the Comparative Examples 1-3 and the blood drug level and the time relation curve of commercially available cefoxitin sodium for injection are shown in the accompanying drawing 1.
Can know by Fig. 1; Compare with commercially available cefoxitin sodium for injection with the MK-306 lipidosome injection for preparing among the Comparative Examples 1-3; The MK-306 lipidosome injection for preparing among the embodiment of the invention 1-3 has the following advantages: elimination speed is in vivo slowed down; Distribution time prolongs in the body circulation, has reached improved slow release effect, and bioavailability increases.
Claims (9)
1. a MK-306 lipidosome injection is characterized in that mainly being processed by MK-306, Phosphatidylserine, cholesterol, poloxamer 188, trehalose.
2. MK-306 lipidosome injection according to claim 1, the specification that it is characterized in that the MK-306 of UD is 0.5g, 1.0g, 2.0g.
3. according to claim 1 or 2 arbitrary described MK-306 lipidosome injections, it is characterized in that processing by the composition of following weight portion:
4. according to the arbitrary described MK-306 lipidosome injection of claim 1-3, it is characterized in that processing by the composition of following weight portion:
5. a method for preparing the MK-306 lipidosome injection is characterized in that comprising the steps:
(1) MK-306, soy phosphatidylserine, cholesterol and poloxamer 188 are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) in bottle, add buffer solution, jolting was stirred 20 minutes; Rotating speed was 500-1000r/min, makes the complete aquation of immobilized artificial membrane, with the even at a high speed matter emulsifying of tissue mashing machine 5-10 minute; Rotating speed 10000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) add trehalose, stir, 0.45 μ m filtering with microporous membrane, packing, lid is rolled in lyophilization, promptly gets the MK-306 lipidosome injection.
6. method for preparing according to claim 5; It is characterized in that; Described organic solvent is selected from one or more in ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, acetonitrile, benzyl alcohol, ethyl acetate, normal hexane and the dichloromethane, is preferably methanol.
7. method for preparing according to claim 5 is characterized in that, described buffer salt solution is selected from a kind of in PBS, citrate buffer solution, carbonate buffer solution, the borate buffer solution.
8. method for preparing according to claim 5 is characterized in that, described buffer salt solution is that pH is 6.8 PBS.
Each described MK-306 lipidosome injection of claim 1-8 in preparation is used for peritonitis and other intraperitoneal, pelvic cavity clinically, gynecological infection; Septicemia; Endocarditis, urinary tract infection (comprising gonorrhea), respiratory tract infection; Bone joint infection, the application in the medicine of skin soft-tissue infection treatment.
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| CN107019700A (en) * | 2017-04-20 | 2017-08-08 | 广东金城金素制药有限公司 | A kind of children use C16H16N3NaO7S2Pharmaceutical entities composition and preparation |
| CN107095874A (en) * | 2017-04-20 | 2017-08-29 | 广东金城金素制药有限公司 | A kind of children use C18H16N8Na2O7S33.5H2O pharmaceutical entities composition and preparation |
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| CN113384705A (en) * | 2021-06-28 | 2021-09-14 | 西南大学 | Preparation of poloxamer modified liposome and application of poloxamer modified liposome in oral drug delivery |
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| CN102895182A (en) * | 2012-10-22 | 2013-01-30 | 四川制药制剂有限公司 | Method for preparing cefoxitin sodium for injection |
| CN107019700A (en) * | 2017-04-20 | 2017-08-08 | 广东金城金素制药有限公司 | A kind of children use C16H16N3NaO7S2Pharmaceutical entities composition and preparation |
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| CN107019700B (en) * | 2017-04-20 | 2018-07-06 | 广东金城金素制药有限公司 | A kind of pediatric pharmaceuticals compositions and preparation |
| CN107115345B (en) * | 2017-04-20 | 2018-07-06 | 广东金城金素制药有限公司 | A kind of pediatric pharmaceuticals compositions and preparation |
| CN107412232B (en) * | 2017-04-20 | 2019-12-03 | 广东金城金素制药有限公司 | A kind of children use C20H18N6Na2O7S4Pharmaceutical entities composition and preparation |
| CN109875963A (en) * | 2019-03-27 | 2019-06-14 | 上海欣峰制药有限公司 | A kind of ceftriaxone injection and preparation method thereof |
| CN109875963B (en) * | 2019-03-27 | 2021-03-30 | 上海欣峰制药有限公司 | Ceftriaxone sodium injection and preparation method thereof |
| CN113384705A (en) * | 2021-06-28 | 2021-09-14 | 西南大学 | Preparation of poloxamer modified liposome and application of poloxamer modified liposome in oral drug delivery |
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